Interest in platinum-based antitumor drugs has its origin in the discovery of the inhibitory effects of platinum complexes on cell division. Subsequent research and development led to the approval of the use of cisplatin, [PtCl2(NH3)2] for cancer therapy. Cisplatin is now widely accepted and is one of the three most widely utilized antitumor drugs in the world. However, cisplatin has several disadvantages that include severe toxicity such as nephrotoxicity, neurotoxicity and emetogenesis. Cisplatin also has limited aqueous solubility (1 mg/ml) and is effective in a narrow range of tumors. Some tumors have natural resistance to platinum drugs while others develop resistance after the initial treatment.
In addition to cisplatin, carboplatin or diammine[1,1-cyclobutanedicarboxylato (2-)]-O,O′-platinum(II) has also received worldwide approval for use in cancer therapy. Carboplatin is less toxic than cisplatin and has greater aqueous solubility (14 mg/ml) but it is still only active in the same range of tumors as cisplatin. Many platinum complexes have been studied in an attempt to overcome the limitation of cisplatin (Wong, E.; et al., Chem. Rev. 1999, 9, 2451-2466).
A class of platinum compounds that has been reported to have activity against cancer is mixed amine platinum complexes of the general formula Pt(L)(L′)A2 or Pt(L)(L′)A2B2 where L and L′ are different amines, and where one of the amines sterically hinders access of Pt to the DNA of the tumor cell. One example within this class of compounds is cis-ammine(2-methylpyridine)dichloroplatinum(II) (Holford, J. F.; et al., Anti-Cancer Drug Des. 1998, 13, 1 and Raynaud, F. I., et al., Clin. Cancer Res. 1997, 3, 2063-2074 and Holford, J. F., et al., Br. J. Cancer 1998, 77, 366 and U.S. Pat. No. 5,665,771). Other examples of antitumor compounds are bis-acetato-ammine(cyclohexylamine)dichloroplatinum(IV) and bis-butyrato-ammine(cyclohexylamine)dichloroplatinum(IV) (Kelland, L. R.; et al., Cancer Res. 1992, 52, 3857; Kelland, L. R., et al., Cancer Res. 1992, 52, 822; Kelland, L. R.; et al., Cancer Res. 1993,53, 2581 and U.S. Pat. No. 5,244,919.
The mixed amine platinum compounds have been reported to have antitumor activity in cisplatin resistant tumors. To compare the ability of various compounds to overcome platinum drug resistance, resistance factors are calculated for sets of cell lines. The resistance factor is defined as the ratio:                activity      ⁢                           ⁢      against      ⁢                           ⁢      a      ⁢                           ⁢      parent      ⁢                           ⁢      line      ⁢                           ⁢      of      ⁢                           ⁢      cancer      ⁢                           ⁢      cells                                            activity            ⁢                                                   ⁢            against            ⁢                                                   ⁢            a            ⁢                                                   ⁢            derivative            ⁢                                                   ⁢            of            ⁢                                                   ⁢            that            ⁢                                                   ⁢            cell                                                            line            ⁢                                                   ⁢            that            ⁢                                                   ⁢            has            ⁢                                                   ⁢            developed            ⁢                                                   ⁢            resistance            ⁢                                                   ⁢            to            ⁢                                                   ⁢            cisplatin                              
Thus, small resistance factors are preferred since the compound is better able to overcome the drug resistance of the cancer cells. The above cited compounds, Cis-ammine(2-methylpyridine)dichloroplatinum(II), bis-acetatoammine(cyclohexylamine)dichloroplatinum(IV) and bis-butyratoammine-(cyclohexylamine)dichloroplatinum(IV) were reported to have activity in certain cisplatin resistant tumors, but do not have equivalent activity in all cancer cells with different mechanisms of platinum drug resistance. For example, bis-acetato-ammine(cyclohexylamine)dichloroplatinum(IV) and bis-butyrato-ammine(cyclohexylamine)dichloroplatinum(IV) have lower resistance factors in the set of 41 M/41 MR cancer cell lines than in the A2780/A2780R or CH1/CH1R sets of cells. On the other hand, cis-ammine(2-methylpyridine)dichloroplatinum(II) has a higher resistance factor in A2780/A2780R cell lines than in the 41M/41MR and CH1/CH1R cell lines. The platinum drug resistance in 41 MR cells is due to reduced platinum accumulation, while in CH1R cells, the resistance is due to enhanced removal of and/or increased tolerance to Pt-DNA adducts. Resistance in A2780R cancer cells is due to detoxification via elevated glutathione levels, decreased uptake and increased DNA repair.
Despite the improved activity of these mixed amine platinum compounds compared to cisplatin in some platinum drug resistant cancer cells, their solubility in aqueous solution is limited; their aqueous solubility at ambient temperature and neutral pH are even lower than that of cisplatin. The limited aqueous solubility poses difficulties in the formulation and administration of these compounds. In particular, the iv administration of a platinum drug with low aqueous solubility may require the infusion of a large volume of liquid in order to achieve the therapeutic dose; a potentially long and inconvenient process.
Increasing the water solubility of platinum antitumor compounds has been an important practical objective of many platinum drug development programs. The solubility of cisplatin (˜1 mg/ml) approaches the practical limit of solubility for a cytoxic agent of its potency that is administered parenterally. Orally administered compounds can be less soluble, but they must be soluble enough to be absorbed. There is a desire to design platinum drugs with improved aqueous solubility as well as improved antitumor activity, particularly in cisplatin resistant tumors.
U.S. Pat. No. 5,665,771 describes and claims a genus which contains the compounds of the present invention. The invention compounds, however, are not specifically taught or suggested in the above-referenced patent, and have improved solubility and/or antitumor activity characteristics as compared to the compounds exemplified in the '771 patent.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein.